The Role of Histamine in Mental Illness and its Attenuation with Vitamin C - Part I

A Dissertation Submitted in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy

Clayton College of Natural Health    

 Birmingham, Alabama     2005

Abstract

The prevalence of mental illness in America is increasingly becoming recognized as an epidemic. There are a number of conventional methods to deal with mental illness, including psychotherapy and pharmaceutical medications. However, both of these types of treatments have their limitations, and pharmaceutical drugs can have many dangerous side effects. Natural therapies have much less side effects than conventional medications, although they have traditionally been used to treat specific mental illnesses. Vitamin C is nontoxic, easily tolerated, and in theory will help the vast majority of mental illnesses. Vitamin C has both mild stimulant and potent antihistamine properties. High histamine levels are associated with both anxiety and depression, and high histamine levels have been shown to be significantly lowered with megadoses of vitamin C. Indeed, vitamin C has been shown to act as both a mild antidepressant and anxiolytic. Its mild stimulant property is due to its boosting of cyclic adenosine monophosphate (cAMP) via inhibition of the enzyme that degrades cAMP, phosphodiesterase. Vitamin C also is involved in the production of the hormone norepinephrine, which is necessary for mental health.

Vitamin C is known to be a key nutrient for proper brain function. Besides keeping histamine levels in check, vitamin C also modulates dopamine levels; high dopamine levels are associated with psychosis. Vitamin C also boosts oxytocin levels, which is involved in pleasure and well-being. Vitamin C protects against neuronal damage, usually via its antioxidant property. Vitamin C inhibits release of the stress hormone cortisol, chronically high levels of which are associated with depression. High blood levels of vitamin C are associated with a significant reduction in death rate. There is no reliable evidence for vitamin C causing DNA mutations, rebound scurvy, iron overload, vitamin B-12 deficiency, or uric acid buildup. The vast majority of animals synthesize their own vitamin C, and animals weighing the equivalent of a human produce roughly a dozen grams of vitamin C daily. This fact adds weight to the theory that humans should megadose with vitamin C, especially if they have mental illness.

Table of Contents

Chapter 1: Introduction to the Problem or Issue...............................................2

Statement of the Problem or Issue......................................................................2

Background and History.........................................................................................5

Research Questions...............................................................................................8

Hypothesis................................................................................................................9

The Significance of the Study................................................................................9

Definition of Terms..................................................................................................9

Summary.................................................................................................................12

Chapter 2: Review of Related Literature and Research................................14

Introduction.............................................................................................................14

Literature Review...................................................................................................29

Summary.................................................................................................................41

Chapter 4: Results and Findings.......................................................................45

Introduction.............................................................................................................45

Findings..................................................................................................................45

Summary................................................................................................................48

Chapter 5: Conclusions, Implications

and Recommendations for Further Research................................................52

Conclusions and Implications...........................................................................52

Recommendations for Further Research........................................................55

Summary................................................................................................................58

References Cited..................................................................................................61

List of Tables, Illustrations and Other Graphics

Abbreviations and Definitions............................................................................10

Chapter 1: Introduction to the Problem or Issue

Statement of the Problem or Issue:

The general purpose of this dissertation is to determine if high intake of Vitamin C alone can help resolve mental illness in general, especially in atopic (allergic) people. Mental illness is a significant problem in today’s society, and a growing body of evidence indicates that nutritional therapies may partially or completely resolve this issue. Many nutrients affect both mental health and the immune system, and it is now well-known that the central nervous system (CNS) and the immune system are intimately linked. The immune system plays a role in regulating feeding behavior, sleep, body temperature, and brain activity (Steinman, 2004). As will be discussed later, histamine is involved in all of the above activities.

A group of peptide hormones called interleukins are prime examples of CNS/immune system interactions. For example, when the immune hormone “IL-2 is given to normal individuals, it produces schizophrenia-like symptoms” (Heleniak & O’ Desky, 1999, p.40). Release of the immune hormone Interleukin-1 beta (IL-1b) can result in depression, learned helplessness, and pain-related behavior (Hurwitz & Morgenstern, 2001). Interleukins are a sub-class of immune hormones termed cytokines. Cytokines can act to create a loss of appetite, malaise, increased sleep, drowsiness, and fatigue (Martin, 1997). A group of cytokines called the interferons (IFNs) are often administered for serious viral infections or cancer. IFN use is associated with depression, insomnia, delirium, and even suicide (McDonald, Mann, & Thomas, 1987). Also, several studies have found that normal white blood cell response to growth factors is impaired in depression, as is natural killer (NK) cell activity (Kagaya & Yamawaki, 1998).  

In order to understand the links between mental health and the immune system, a brief explanation of hormones is needed. There are three main types of hormones: steroid hormones, which are derived from cholesterol, peptide hormones, derived from protein synthesis, and amino-acid derived hormones. The seven major amino-acid derived hormones include: serotonin, norepinephrine (also called noradrenaline), epinephrine (also called adrenaline), dopamine, acetylcholine, gamma-amino butyric acid (GABA), and histamine. The last of these seven amino-acid derived hormones, histamine, will be the primary focus of this dissertation. The reason for this is that histamine is unique among amino-acid derived hormones because it plays prominent roles in both mental status and immune status. Epinephrine and norepinephrine do play certain roles in immune function, but unlike histamine, their roles are generally positive in normal subjects. However, depressed people tend to have higher levels of epinephrine, norepinephrine, and the steroid hormone cortisol (Martin, 1997). This phenomenon will be described in greater detail later. The other four amino-acid derived hormones play only minor roles, if any, in immune status.

Histamine has myriad effects on the body, ranging from subtle to lethal. These effects will be described in detail throughout this dissertation. The complex effects of histamine are due to both its positive and negative effects, depending on the cell type that released it. As mentioned above, histamine is both a neurotransmitter and an immune modulator. Neurotransmitter cells that release histamine are called neurons, and immune modulator cells that release histamine are most often mast cells, although a few other immune cell types also store histamine. Both neurotransmitter histamine and mast cell histamine are found in the brain. Neurotransmitter-released histamine can perform both positive and negative functions, while mast cell-released histamine generally performs negative (morbid/mortal) functions.

It has been discovered that in rat brains, mast cells release histamine during stress (Arrigo-Reina & Chiechio, 1998). Released brain histamine may play a role in both physical dependence and tolerance to morphine (Glick & Crane, 1978). Further evidence of this phenomenon is provided by a combination antihistamine / opioid therapy as a heroin substitute (Galosi et al., 2001). Another intriguing finding is that neurotransmitter histamine tends to decrease with age, while mast cell brain histamine tends to increase with age (Fernandez-Novoa & Cacabelos, 2001). Normal histamine levels play useful physiological roles, but high histamine levels are considered pathological (Subramanian, Nandi, Majumber, & Chatterjee, 1974). Excessive blood histamine levels may raise the overall death rate by 24% (Johnston, 1996).

Elevated brain histamine levels inhibit reward-related behavior (Galosi et al., 2001). This lack of motivation may lead to apathy and depression. Another of the many functions of brain histamine is memory modulation. Local administration of histamine into animal forebrain reinforced fear memory (Blandina et al., 2004). However, histamine can both facilitate and inhibit memory (Blandina et al., 2004). More specifically, histamine usually improves short-term memory (Prast, Argyriou, & Philippu, 1996), while possibly impairing long-term memory. Interestingly, histamine facilitated memory retrieval in old rats (Kamei & Tasaka, 1993).

It is well-known that histamine is involved in allergic and inflammatory reactions (Haas, 1992). A detailed explanation of this effect is in the Introduction section of Chapter 2. There is strong evidence to suggest a link between mental illness and allergies. “Studies of depressed and chronically fatigued patients found that up to 70 percent suffered from allergies---as compared to 2 percent of healthy controls” (Firshein, 1996, p. 160). Another study found that “85% of depressed patients had allergies” (Ossofsky, 1976, p.335). Histamine can cause behavioral depression, and this can be reversed by the antihistamine effects of tricyclic antidepressants (Arrigo-Reina & Chiechio, 1998). Tricyclics have many other actions on neurotransmission as well.

It is well-known that allergies and asthma are strongly linked. An important study found that children with severe asthma have significantly more behavioral problems (Bussing, Halforn, Benjamin, Wells, 1995). Children with early onset asthma, before the age of four, tend to have fearfulness, insomnia, and depressed mood (Mrazek, Schuman, & Klinnert, 1998). Conversely, psychosocial stressors can precipitate asthma (Kilpelainen, Koskenvuo, Helenius, & Terho, 2002), creating a vicious cycle. Intriguingly, behavior problems tend to precede asthma in children (Stevenson et al., 2003). The link between allergies/asthma and behavioral problems can begin as early as age three (Calam et al., 2003).

Background and History:

The application of nutritional therapies to mental illness began in the latter half of the 20th Century, with Drs. Abram Hoffer and Carl Pfeiffer. They recognized that blood histamine levels were low in around 50% of schizophrenic patients, and subsequently designed nutritional therapies for them (Petrie & Ban, 1985). However, many schizophrenics have raised histamine levels. The standard orthomolecular therapy for high histamine levels is calcium, magnesium, methionine, and zinc. It has been known for some time that vitamin C detoxifies excess histamine by cleavage of the imidazole group (Subramanian, 1977). Unfortunately, vitamin C is not one of the main treatments for high histamine levels, and the recommended therapeutic dose is relatively low, at 2000 mg/day. In fact, low histamine levels were treated with higher vitamin C doses (Edelman, 1998).

Histamine’s actions have been studied in both humans and animals. Histamine injected into animal brains caused a variety of behavioral symptoms, including irritability, teeth chattering, grooming, facial tremors, chewing, head shakes, yawning, writhing, and salivation (Glick & Crane, 1978). As mentioned in the previous section, tricyclic antidepressants have been used in the past to reverse histamine-induced depression via their common antihistamine actions. Classical antihistamines are known to decrease anxiety, in that “H1 receptor antagonists and H3 receptor antagonists decrease the anxiety state” (Ito, 2000, p.263). Furthermore, tricyclic antidepressants may lower anxiety (most tricylics have a strong antihistamine effect).

Unfortunately, tricyclic antidepressants have a plethora of side effects, some of which are lethal (Wilson, Shannon, & Stang, 2000). The tricyclic antidepressants can be informally categorized under the ‘first-generation’ of antihistamines, which cross the blood-brain barrier. Side effects of these first-generation antihistamines include dry mouth, drowsiness, restlessness, and sleepiness (Edelman, 1997). One of the most notorious side effects of first-generation antihistamines is weight gain (Tuomisto, 1994). Chronic use of first-generation antihistamines may cause memory loss (Mark & Mark, 1989). Other first-generation antihistamines besides tricyclics have also been used to treat mental illness, specifically anxiety disorders.

The most commonly used antihistamine used in the past for anxiety was Hydroxyzine (Atarax); drowsiness was the most commonly reported side effect (Lader & Scotto, 1998). Over-the-counter first-generation antihistamines have been abused for a variety of reasons, including hallucinations, anxiety-lowering effects, and/or euphoric sensations (Halpert, Olmstead, & Beninger, 2002). The antihistamine diphenhydramine (Nytol, Benadryl) has reportedly been abused by pre-teens (Dinndorf, McCabe, & Frierdich, 1998).

Due to the above problems with the older antihistamines, pharmaceutical companies attempted to design next-generation antihistamines that do not cross the blood-brain barrier, and thus presumably would not have any CNS or brain side effects. In the late 1980’s the first prototype second-generation antihistamines were synthesized. Since the structure of the second-generation antihistamines was more hydrophilic than the older antihistamines, the second-generation antihistamines did not cross the fatty blood-brain barrier to a significant extent, and thus did not cause sedation in most people. They also do not share the anticholinergic effects of the older antihistamines, which can cause dry mouth and thickening of mucus secretions (Wray, 1998; Fried, 1999).

Even the second-generation antihistamines have their share of side effects, which include: drowsiness, sedation, headache, depression, fatigue, nausea, anxiety, hypotension, hypertension, palpitations, tachycardia, vomiting, blurred vision, and rash (Wilson, Shannon, & Stang, 2000). Second-generation antihistamines also can produce altered brain activity that can approach convulsions (Fernandez-Novoa & Cacabelos, 2001). The second-generation antihistamine Fexofenadine (Allegra) can cause life-threatening arrythmias and fibrillation, and “has been withdrawn from the market in several countries” (Taglialatela, Timmerman, & Annunziato, 2000, p.53). Second-generation antihistamines Cetirizine (Zyrtec) and Loratadine (Claritin) have both been shown to cause memory loss (Nishiga, Fujii, Konishi, Hossen, & Chiaki, 2003). Both first- and second-generation antihistamines can cause seizures (Taglialatela, Timmerman, & Annunziato, 2000).

Research Questions:   

The major discrepancy noted above in the beginning of the Background and History section (using vitamin C to treat low histamine levels) may be unique to treating schizophrenia, but unfortunately the historical research has shown that no other form of mental illness has been given the nutritional attention that schizophrenia has. Contemporary research has studied vitamin C from a relatively theoretical level, and it has been determined that vitamin C affects many different aspects of behavior and mental health. It is the goal of this dissertation to suggest various applications for vitamin C in improvement of various mental health issues based on both new information and reevaluation of historical research.

Hypothesis:

Large doses of vitamin C can reduce or reverse most mental illnesses, especially when they are allergy-linked.

Significance of the Study:

Treatment of mental illness with pharmaceutical drugs can be dangerous to the patient. Over half of the main prescription drugs used to treat anxiety and depression have potentially lethal side effects (Jensen, 2002). Pharmaceutical antihistamines have many side effects, some of which were described in the Background and History section of Chapter 1. It would be an accomplishment of major significance if one or more nutrients were safely and successfully used to help most forms of mental illness, and if this information were to be accepted by mainstream health care. Possible impacts of this study include using vitamin C as an adjunct therapy along with other nutrients, or alone as a holistic therapy for various mental illnesses. Potential benefits of the above use of vitamin C could result in a significant decline in morbidity and mortality of prescription drug users, and possibly even resolution of mental symptoms.

Definition of Terms:

The variables in this study include various forms of mental illness, although this study will attempt to take a holistic approach to the treatment of mental illness, and will only mention specific diagnoses if they are essential to understanding the greater issue at hand. There will be many uncommon terms used in the proposed study. Vitamin C will be the term used to describe the molecule ascorbate. If ascorbic acid, sodium or calcium ascorbate, or dehydroascorbate is specifically mentioned or recommended, then those terms will be used instead of vitamin C. There will be many different hormones and proteins named in the study, often with their abbreviations. If a hormone or protein is to be abbreviated throughout the dissertation, it will be introduced initially with its full name, then with its abbreviation from then on. A list of common abbreviations and definitions is provided below.

AA                                           Arachidonic Acid (precursor to prostaglandins)

ACTH                                     Adrenocorticotropic Hormone

ADD                                       Attention Deficit Disorder

ADHD                                    Attention Deficit-Hyperactivity Disorder

Allergen                                Antigen

Antagonist                            Receptor blocker

Axon                                       Presynaptic nerve terminal

BDNF                                     Brain-Derived Neurotrophic Factor

Ca2+                                      Calcium ion

CaM                                        Calmodulin

CAM K’s                                 Calmodulin kinases

cAMP                                       cyclic Adenosine Monophosphate

CNS                                        Central Nervous System

CREB                                      cAMP Response Element Binding Protein

CRH                                        Corticotropin-Releasing Hormone

Cu2+                                       Copper ion

Cytosol                                    The intracellular fluid of a cell and the vast majority of a typical cell’s volume

DAG                                         Diacylglycerol

Dehydroascorbate                Fully oxidized vitamin C

Dendrite                                  Postsynaptic nerve terminal

DGLA                                       Dihomo-Gamma Linoleic Acid

DNA                                         Deoxyribonucleic Acid

GABA                                       Gamma-aminobutyric acid

5-HT                                         5-hydroxytryptamine; serotonin

H                                               Histamine

Histaminemia                        Elevated histamine blood and/or tissue levels

HPA axis                                  Hypothalamic-Pituitary-Adrenal axis

IFN’s                                         Interferons

IgE                                            Immunoglobulin E (anti-allergen antibody)

IL-1b                                         Interleukin -1 Beta

IP3                                            Inositol triphosphate

Kinase                                     A protein that transfers a phosphate group to another protein or small molecule

Lipid                                         Fat

LTD                                           Long-term Depression (of neural activity)

LTP                                           Long-term Potentiation (of neural activity)

MAP2                                        Microtubule-associated Protein 2

mRNA                                      messenger Ribonucleic Acid

NK cells                                   Natural Killer cells

NMDA                                       N-Methyl-D-aspartate

Paracrine                                 Local hormone action

PLC                                          Phospholipase C

PGE1                                       Prostaglandin E1

PGF2a                                     Prostaglandin GF2a

PIP2                                         Phosphatidylinositol 4,5-bisphosphate

PKA                                          Protein Kinase A

PKC                                         Protein Kinase C

PRL                                          Prolactin

SAMe                                       S-Adenosylmethionine

Synapse                                  Intracellular space between neurons

Th1                                           T-helper 1 immune response; the classical immune response against microbes

Th2                                           T-helper 2 immune response; the classical ‘allergic’ IgE-mediated immune response against allergens

Transcription                           RNA is made from a DNA template

Translation                              Expression of protein from mRNA

Vitamin C                                 Ascorbic acid, ascorbate

Summary:

The main issue in this dissertation is whether or not vitamin C can significantly attenuate histamine-related mental illness. Many different nutritional supplements have been successfully used in resolving mental illness (Edelman, 1998). However, the literature does not show vitamin C ever being used as a main-line nutritional therapy for any kind of mental illness. The antihistamine effect of vitamin C has not been effectively utilized in the past by the vast majority of either conventional or alternative practitioners. Conversely, the fact that relatively small amounts of vitamin C can release histamine has been used as a therapy in schizophrenic patients that have abnormally low histamine levels. Unfortunately, the practitioners that used this therapy did not use high-dose vitamin C therapy for schizophrenics with high histamine levels. Presumably this is because they believed that the extra doses of vitamin C may release even more histamine, and they also may not have been aware of vitamin C’s antihistamine effects at doses of several grams/day.

There is much evidence to support numerous interactions between the brain and the immune system. Abnormal amounts of immune hormones can cause schizophrenia and/or depression (Heleniak and & O’Desky, 1999; Hurwitz & Morgenstern, 2001). Of the amino-acid derived hormones that are both neurotransmitters and immunomodulators, histamine is by far the most important. It has been hypothesized that histamine is involved in mental illness (Pfeiffer, 1987), and it has long been proven that histamine is a major instigator of immune abnormalities/overreactions (Haas, 1992). In congruence with previous data suggesting a genetic basis for schizophrenia, there appears to be a genetic basis for some histamine-related schizophrenia (Brown, Stevens, & Haas, 2001). One theory of schizophrenia is that the blood-brain barrier is compromised, allowing unwanted molecules into the brain. Histamine has been shown to disrupt the blood-brain barrier (Greenwood, 1991). In the past decade, much research has been conducted into the classic stress-related ‘fight-or-flight’ response. Histamine has been found to be an important promoter of this morbid response (Johnston, Retrum, & Srilaskshmi, 1992).

Histamine can cause a variety of behavioral abnormalities in both humans and animals, and some of these abnormalities can be reversed by pharmaceutical antihistamines (Lader & Scotto, 1998). Unfortunately, pharmaceutical antihistamines have several side effects, and the more dangerous ones can be lethal (Wilson, Shannon, & Stang, 2000). Even the relatively safer second-generation pharmaceutical antihistamines have their share of side effects (Wilson, Shannon, & Stang, 2000). Since the second-generation antihistamines do not cross the blood-brain barrier to an appreciable extent, they cannot be used to treat mental illness. Vitamin C has potent antihistamine effects, does cross the blood-brain barrier, and has very mild side effects, if any. There is also both anecdotal and epidemiological evidence that vitamin C supplementation improves mental health (Mark & Mark, 1989; Balch & Balch, 1997; Brody, 2002). It would seem from the above information that vitamin C supplementation should be included in every mental illness therapy regimen.